It has been suggested that the airway contractile response of asthmatic subjects to a deep inspiration, compared to normal airway dilation seen in healthy subjects, reflects an intrinsic pathophysiology of this disease. Although it is clear that properties of airway smooth muscle must be involved in this functional difference, the properties of the parenchyma that surround the airways may be equally important. This fact suggests that a significant problem in asthma may be related to airway smooth muscle behavior in its dynamic parenchymal environment. This proposal will evaluate mechanisms that underlie this parenchymal-airway interaction, particularly focused on the response to lung inflation and deep inspiration with contracted smooth muscle. This project contains several unique approaches to provide new information on how the lung responds to distension in vivo. First we use a novel method of challenging individual airways that allows us to separate the effects of agonist stimulation on individual airways, the entire airway tree, or the lung parenchyma. Second, by simultaneously using CT imaging with lung impedance measurements, we will be able to completely characterize the airway and dynamic parenchymal viscous and elastic responses. Third, by using a novel challenge method to anesthetize local airway nerves, we can determine how these nerves interact to determine whether the airway will respond with a contraction or relaxation following a deep inspiration. Specific aims of this proposal are designed to test two primary hypotheses related to this airway-parenchymal interaction in vivo: 1) The resultant behavior of airways following lung inflation depends on a balance between opposing physical and chemical effects on the smooth muscle;2) parenchymal contraction can limit the ability of airways to narrow with pharmacologic or inflation stresses.